In spite of the wealth of experimental, clinical and epidemiological data that have helped identify important genetic components and pathways in colorectal cancer (CRC), CRC continues to be the second leading cause of cancer associated death, with close to 50,000 deaths predicted for the year 2008 in the US alone. Because CRC arises predominantly in benign precursors (mainly the adenomatous polyps), which are likely to sojourn for many years before they turn malignant, CRC can be prevented largely through screening and prompt intervention. The goal of this renewal is to further explore, via a biomathematical description of the natural history of CRC, how screening and interventions can be applied most effectively to reduce the mortality associated with CRC PUBLIC HEALTH RELEVANCE: Relevance from a clinical and public health perspective, the overarching goal of this renewal is to further develop and validate biomathematical models of the natural history of colorectal cancer for quantitative cancer risk prediction. These models are also meant to help clinicians manage cancer surveillance and interventions in patients with screen-detected precursor lesions and pre-clinical cancer.